Overview

Dr. Deng’s research program is primarily focused on investigating bile acid and cholesterol homeostasis under physiological and pathological conditions. Disruption of bile acids and cholesterol homeostasis by genetic or environmental factors has been associated with various diseases, including intrahepatic cholestasis, hypercholesterolemia, gallstone disease, hepatic cellular carcinoma (HCC) and metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) and diabetes. Farnesoid X receptor (FXR) is the master regulator of bile acid homeostasis while estrange receptor a (ERa) cross-talks with FXR signaling. Bile salt export pump (BSEP) is responsible for biliary excretion of bile acids and plays a critical role in maintaining intrahepatic as well as systemic bile acid levels. The long-term goal of this research program is to understand bile acid regulation by FXR and ERa signaling and bile acids-associated diseases.

Research

Project 1: Estrogen-mediated transrepression of BSEP and its role in intrahepatic cholestasis of pregnancy and gallstone disease

Among diseases resulted from imbalance of bile acid levels, intrahepatic cholestasis of pregnancy (ICP) and gallstone disease are both associated with sex hormone estrogens. ICP predominantly occurs during the third trimester of pregnancy correlating with elevated estrogen levels. Gallstone disease exhibits clear gender preference with women being 2-3 times more susceptible than men. Although multiple risk factors are linked to those disorders, studies have demonstrated that estrogen plays a key role in the induction of the two diseases. We have found that BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition in mice, resembling the clinical course of ICP in humans. Furthermore, the transcriptional dynamics of BSEP was inversely correlated with serum 17b-estradiol (E2) levels before, during and after gestation. In this project funded by an NIH R01 grant, we investigate the underlying mechanisms by which BSEP is transrepressed by estrogens and its etiological role in the development of ICP and gallstone disease.

Project 2: Isoform  specific regulations of BSEP by FXR and its association with dysergulation of bile acids in patients with HCC

BSEP expression is regulated by the bile acid nuclear receptor farnesoid X receptor (FXR). Four isoforms of FXR have been identified with predominant expression of FXRa1 and FXRa2 in the liver. Clinical studies showed that bile acid homeostasis is disrupted in HCC patients with elevated serum bile acid level as a proposed marker for HCC. We found that BSEP expression was severely diminished in HCC tissues correlated with altered FXR isoform expression levels (FXRa1/FXRa2 ratio). In this project, we investigate the isoform-specific regulation of FXR target genes including BSEP by FXR and its implications in molecular pathogenesis of HCC. 

Project 3: Dysregulation of ubiquitin carboxyl-terminal hydrolase 2 (USP2) in association with FXR and ERa signaling in HCC pathogenesis

Both FXR and ERa signaling are linked to HCC. A large body of evidence supports that both FXR and ERa signaling provide protection against HCC development. Indeed, FXR knockout (FXR-KO) mice spontaneously developed HCC as they aged while ERa-KO mice exhibited increased susceptibility to chemical-induced HCC. Consistent with their protective roles, FXR and ERa signaling were dysregulated or defective in large percentages (60-80%) of HCC patients with decreased or total lack of FXR or ERa expression with concurrent switches to its variants or different isoforms.  As a member of deubiquitinating enzymes (DUBs), USP2 removes ubiquitin from ubiquitinated target proteins, thus preventing proteosomal degradation of the target proteins, as a result increasing the target protein levels. We found that USP2 is transcriptionally regulated by FXR and ERa signaling and USP2 expression is dysregulated in HCC patients. In this project, we are aiming at establishing a signaling pathway from FXR/ERa to USP2 and its downstream targets in the development of HCC using FXR and ERa-knockout as well as FXR/ERa-double knockout mouse models. 

Project 4: Understanding the molecular linkage between dysregulation of bile acids in patients with liver diseases and preterm birth in pregnant women

Preterm birth (PTB) is defined as babies born before 37 weeks of pregnancy (gestation) and is the leading cause of perinatal mortality worldwide. Surviving preterm infants are also at risk for neurological, respiratory and gastrointestinal complications, metabolic syndrome and cardiovascular disease. The underlying mechanisms by which PTB is induced are complex and multi-factorial.  Despite current research efforts, our understanding on the underlying mechanisms for PTB remains limited. Pregnant women with ICP and other liver diseases including NAFLD had increased risk for PTB. We found that serum total bile acid levels directly correlated with the PTB rates of pregnant women regardless of the characteristics of the subjects. In this project, we are investigating etiological linkage between bile acids and PTB with a long-term goal to uncover the underlying mechanisms by which bile acids induce PTB and develop therapeutic interventions to prevent or delay PTB in pregnant women with liver disorders. 

Project 5: Transcriptional regulations of AKR1D1 under physiological and pathological conditions.

AKR1D1 (aldo-keto reductase family 1, member D1) is required for cholesterol metabolism to bile acids and acts on a divergent point for the synthesis of two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). Consistent with its vital role in bile acid synthesis, newborns with deficiency in AKR1D1 develop severe cholestatic liver disease. In addition to bile acid concentration, its composition plays a critical role in regulating cholesterol and bile acid homeostasis. Dysregulation of CA and CDCA synthesis is reported in various diseases including cholestasis, diabetes and HCC. As the two primary bile acids, CDCA and CA exhibit different, sometimes even opposite, effects on cholesterol and bile acid regulation. It becomes evident that AKR1D1 plays a determinant role in the relative synthesis of CA and CDCA and is involved in the regulation of bile acid and cholesterol homeostasis. In this project, we investigate the transcriptional regulation of AKR1D1 under physiological as well as disease conditions such as diabetes and HCC.

Project 6: Development of drug and siRNA delivery systems.

In collaborating with faculty from chemistry, chemical engineering and pharmaceutics, we investigate various drug and siRNA delivery systems including bilayer-decorated magnetoliposomes with trigger-releasing, golden nanoparticles and chiral cationic polyamines.

Publications

1. Valanejad L, Ghareeb M, Shiffka S, Nadolny C, Chen Y, Guo L, Verma R, You S, Akhlaghi F, Deng R (2018). Dysregulation of Δ4-3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms. Mol Cell Endocrinol. 470:127-141.
2. Zhang X and Deng R (2018). Dysregulation of bile acids in patients with NAFLD. In the book of “Nonalcoholic Fatty Liver Disease-An Update”, edited by Emad Hamdy Gad. IntechOpen Publisher. ISBN 978-953-51-7795-1.
3. Deng R (2017). Bile salt export pump: drug-induced liver injury and assessment approaches. In the book of “Drug-Induced Liver Toxicity”, edited by Minjun Chen and Yvonne Will. In the book series of “Methods in Pharmacology and Toxicology”. Humana Press. Humana Press, New York, NY. ISBN 978-1-4939-7676-8.
4. Zheng K, Lu P, Delpapa E, Bellve K, Deng R, Condon JC, Fogarty K, Lifshitz LM, Simas TAM, Shi F, ZhuGe R (2017). Bitter taste receptors as targets for tocolytics in preterm labor therapy. FASEB J. 31(9):4037-4052.
5. Zhang G, Liu S, Tan W, Verma R, Chen Y, Sun D, Huan Y, Jiang Q, Wang X, Wang N, Xu Y, Wong C, Shen Z, Deng R, Liu J, Zhang Y, Fang W (2017). Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists. Eur J Med Chem. 129:303-309.
6. Valanejad L, Nadolny C, Shiffka S, Chen Y, You S, Deng R (2017). Differential Feedback Regulation of Δ4-3-Oxosteroid 5β-Reductase Expression by Bile Acids. PLoS One. 12:e0170960. PMC5268776.
7. Song X, Vasilenko A, Chen Y, Valanejad L, Verma R, Yan B and Deng R (2014) Transcriptional Dynamics of Bile Salt Export Pump during Pregnancy: Mechanisms and Implications in Intrahepatic Cholestasis of Pregnancy. Hepatology. (In Press)
8. Chen Y, Chen Y, Xiao D, Bose A, Deng R and Bothun GD (2014). Low-Dose Chemotherapy of Hepatocellular Carcinoma In Vitro through Triggered-Release from Bilayer-Decorated Magnetoliposomes. Colloids Surf B Biointerfaces. 116C:452-458.
9. Song X, Chen Y, Valanejad L, Kaimal R, Yan B and Deng R (2013) Mechanistic Insights into Isoform and species-specific regulation of bile salt export pump by farnesoid X receptor. J Lipid Res. 54:3030-3044.
10. Chen Y, Song X, Valanejad L, Vasilenko A, More V, Qiu X, Chen W, Lai Y, Slitt A, Stoner M, Yan B, Deng R (2013) Bile salt export pump is dysregulated with altered farnesoid X receptor isoform expression in patients with hepatocellular carcinoma. Hepatology. 57:1530-1541.
11. Gharavi J, Marks P, Moran K, Kingsborough B, Verma R, Chen Y, Deng R, Levine M (2013) Chiral cationic polyamines for chiral microcapsules and siRNA delivery. Bioorg Med Chem Lett. 23:5919-5922.
12. Deng R (2012) Pharmacy research at URI: bile acids and bile salt export pump: physiology and pathology. Med Health R I. 95:290-291.
13. Yang D, Yang J, Shi D, Deng R and Yan B (2012) Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of cholesteryl ester hydrolase ces1 and bile salt export pump. J Lipid Res. 53:529-539.
14. Deng R (2012) A review of the hypoglycemic effects of the five commonly used herbal food supplements. Recent Pat Food Nutr Agric. 4: 50-60.
15. Yang D, Yang J, Shi D, Deng R, Yan B (2011) Scoparone potentiates transactivation of the bile salt export pump gene and this effect is enhanced by cytochrome P450 metabolism but abolished by a PKC inhibitor. Br J Pharmacol. 164:1547-1557.
16. Deng R and Chow TJ (2010). Hypolipidemic, Antioxidant and Antiinflammatory Activities of Spirulina Microalgae. Cardiovasc Ther. 28: e33-45.
17. Yang D, Wang X, Chen YT, Deng R and Yan B (2009) Pyrethroid insecticides: isoform-dependent hydrolysis, induction of cytochrome P450 3A4 and evidence on the involvement of the pregnane X receptor. Toxicol Appl Pharmacol. 237:49-58.
18. Kaimal R, Song X, Yan B, King R and Deng R (2009) Differential Modulation of Farnesoid X Receptor Signaling Pathway by Thiazolidinediones. J Pharmacol Exp Ther. 330:125-134.
19. Yu BZ, Kaimal R, Bai S, Sayed KA, Tatulia SA, Apitz R, Jain M, Deng R and Berg OG (2009) Effect of bile salts and cembrenes on FXR and PLA2: Role in Catabolic homeostasis of cholesterol. J Nat Prod. 72:24-28.
20. Deng R (2009) Food and food supplements with hypocholesterolemic effects. Recent Patents on Food, Nutrition & Agriculture. 1:15-24.
21. Liu FJ, Song X, Yang D, Deng R, Yan B (2008) The far and distal enhancers in the CYP3A4 gene coordinate the proximal promoter in responding similarly to the pregnane X receptor but differentially to hepatocyte nuclear factor-4alpha. Biochem J. 409:243-250.
22. Song X, Kaimal R, Yan B and Deng R (2008) Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression. J Lipid Res. 49:973-984.
23. Deng R, Radke A, Yang J and Yan B (2007) Hypolipidemic Agent Guggulsterone Regulates the Expression of Human Bile Salt Export Pump: Dominance of Transactivation over FXR-Mediated antagonism. J Pharmacol Exp Ther. 320:1153-1162.
24. Deng R (2007) Therapeutic effects of guggul and its constituent guggulsterone: cardiovascular benefits. Cardiovascular Drug Reviews. 25:375-390.
25. Deng R, Yang D, Yang J, Yan B (2006) Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor FXR but not LXR. J. Pharmacol. Exp. Ther. 317: 317-325.
26. Li Y, Xie M, Yang J, Yang D, Deng R, Wan Y, Yan B (2006) The expression of antiapoptotic protein survivin is transcriptionally upregulated by DEC1 primarily through multiple sp1 binding sites in the proximal promoter. Oncogen. 25: 3296-3306.
27. Ma Y, Song X, Sachdeva K, Liu J, Li Y, Yang D, Deng R, Chichester CO, Yan B (2005) Clofibrate and perfluorodecanoate both up-regulate the expression of the pregnane X receptor but only clofibrate enhances its ligand-dependent induction of cytochrome P4503A23. Biochem. Pharmacol. 69, 1363-1371.

Ruitang Deng, Ph.D.

• Professor
• Phone: 401.874.4950
• Email: dengr@uri.edu